New therapeutic targets in ovarian cancer stem cells

Whether classifi ed as “tumor-initiating” cells, “cancer stem-like” cells or simply “cancer stem cells” (CSCs), this small population of highly undiff erentiated and slow cycling cells is implicated in early molecular events linked to cancer development as well as in tumor progression, recurrence, and development of chemotherapy resistance (1). During the last decade an increasing amount of scientifi c reports yielded proof of existence of a subpopulation of cells within tumors bearing the main characteristics of stem cells in normal tissues: quiescence and capacity of self-renewal and diff erentiation (2). Specifi c signaling pathways controlling normal stem cells identity were found to regulate the phenotype of this subset of tumor cells bearing “stemness” features (3). Th e fi rst report documenting a cancer initiating cell phenotype in solid tumors was published in 2003 in a breast cancer model (4). CD44high/CD24low cells are characterized by self-renewal properties, tumor initiating capacity in vivo, when injected in small numbers (50-100) in NOD/SCID mice, and ability to diff erentiate into cells with more specifi c phenotypes and functions. Since that report, the fi eld expanded to include most solid tumors, continuously refi ning the cancer stem cell hypothesis. However, the very existence of CSCs remains controversial, as researchers have struggled to defi ne similarities and distinct traits between normal and cancer stem cells (5). Although CSCs were described by Hans Clevers as “malignant equivalents of tissue stem cells” (6), it remains open for debate whether cancer occurs by mutations in normal tissue-specifi c stem cells or whether transformation follows in transit amplifying cells or even in more committed cells driving their dediff erentiation to stem-like cancer cells (7, 8). It is accepted that CSCs represent a rare cell population within tumors, however their precise quantifi cation has been variable. Th e most extreme report comes from the melanoma models, suggesting that CSCs can recapitulate Abstract Ovarian cancer (OC) is the deadliest gynecological malignancy. Characterized by frequent recurrences after standard chemotherapy and a pattern of dissemination in the peritoneal cavity, ovarian tumor development and progression may be driven by cancer stem cells (CSCs). This concept is supported by the identification of a subset of OC cells with stem-like characteristics, including self-renewal, ability to differentiate and to initiate tumors in vivo. It has been proposed that ovarian CSCs are responsible for development of chemotherapy resistance and of disease recurrence, which occur commonly in OC. Several markers are used for the isolation of ovarian CSCs and distinct pathways fuel their survival and proliferation within the tumor microenvironment (TME). Here we aim to review recent advances in the field of ovarian CSCs and to discuss novel therapeutic targets which could be exploited to eliminate this tumor cell sub-population with the goal of preventing emergence of resistance to chemotherapy and disease progression.